The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by a-PD-L1 or a-IL6 antibodies

Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted
by activated macrophages and dendritic cells.We show that IL27 induces STAT factor phosphorylation
in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation
and recapitulates an IFN-𝛾-like response in the microarray analyses, with up-regulation of genes
involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-𝛾, IL27
leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune
clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1,
which are associatedwith immune escape of cancer. Interestingly, differential expression of these
geneswas observed within the different cell lines and when comparing IL27 to IFN-𝛾. In coculture
experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells,
pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28
activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion.
The levels of other TH1 cytokines were also enhanced or restored upon administration of
anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine prestimulation—
mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor
inflammation–induced cachexia—can be antagonized by antibodies against IL6-type cytokines
or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased
antigen presentation) might thus be increased by combining IL27with blocking antibodies against
PD-L1 or/and IL6-type cytokines.